Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, 715 Sumter St., Columbia, SC 29208, United States.
Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, 715 Sumter St., Columbia, SC 29208, United States.
Acta Biomater. 2018 Mar 1;68:113-124. doi: 10.1016/j.actbio.2017.12.023. Epub 2017 Dec 30.
Disulfiram (DSF), an FDA approved drug for the treatment of alcoholism, degrades to therapeutically active diethyldithiocarbamate (DDTC) in the body by reduction. Hereby, we developed a redox sensitive DDTC-polymer conjugate for targeted cancer therapy. It was found that the DDTC-polymer conjugate modified with a β-d-galactose receptor targeting ligand can self-assemble into LDNP nanoparticle and efficiently enter cancer cells by receptor-mediated endocytosis. Upon cellular uptake, the LDNP nanoparticle degrades and releases DDTC due to the cleavage of disulfide bonds, and subsequently forms copper (II) DDTC complex to kill a broad spectrum of cancer cells. 3D cell culture revealed that this nanoparticle shows much stronger tumor mass penetrating and destructive capacity. Furthermore, LDNP nanoparticles exhibited much greater potency in inhibiting tumor growth in a peritoneal metastatic ovarian tumor model.
The β-d-galactose receptor targeted disulfiram loaded nanoparticle (LDNP) is novel in the following aspects.
双硫仑（DSF）是一种经 FDA 批准用于治疗酗酒的药物，在体内通过还原作用降解为具有治疗活性的二乙二硫代氨基甲酸盐（DDTC）。在此基础上，我们开发了一种氧化还原敏感的 DDTC-聚合物缀合物用于靶向癌症治疗。研究发现，用 β-d-半乳糖受体靶向配体修饰的 DDTC-聚合物缀合物可以自组装成 LDNP 纳米颗粒，并通过受体介导的内吞作用有效地进入癌细胞。进入细胞后，由于二硫键的断裂，LDNP 纳米颗粒降解并释放 DDTC，随后形成铜（II）DDTC 络合物杀死广谱癌细胞。3D 细胞培养显示，这种纳米颗粒具有更强的肿瘤穿透和破坏能力。此外，LDNP 纳米颗粒在抑制腹膜转移性卵巢肿瘤模型中的肿瘤生长方面表现出更强的效力。
β-d-半乳糖受体靶向双硫仑负载纳米颗粒（LDNP）在以下几个方面具有新颖性。
